Understanding Antiretroviral Therapy (ART)
Antiretroviral therapy is a combination of medications from different drug classes that suppress HIV replication, allowing people with HIV to live near-normal lifespans when taken consistently. 1
What ART Does
ART works by blocking different steps in HIV's replication cycle, which:
- Suppresses viral load to undetectable levels (preventing transmission)
- Restores and preserves immune function (increases CD4+ counts)
- Prevents progression to AIDS
- Reduces mortality to near that of the general population 1
The Six Drug Classes
ART consists of six mechanistic classes that target different stages of the HIV lifecycle 1:
- Entry inhibitors - Block HIV from entering cells
- Nucleoside reverse transcriptase inhibitors (NRTIs) - Stop viral DNA synthesis
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Also block reverse transcriptase but differently
- Integrase strand transfer inhibitors (InSTIs) - Prevent viral DNA integration into human DNA
- Protease inhibitors (PIs) - Block viral protein assembly
- Capsid inhibitors - Newest class targeting viral capsid
Current Preferred Regimens
The 2024 IAS-USA guidelines recommend integrase inhibitor-based regimens as first-line therapy 2. Modern regimens are:
- Single-tablet, once-daily combinations for convenience
- Built around high-barrier-to-resistance InSTIs (bictegravir or dolutegravir)
- Combined with 1-2 NRTIs (typically tenofovir + emtricitabine or lamivudine)
Specific first-line options include:
- Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF)
- Dolutegravir-based combinations (DTG/3TC or DTG with tenofovir/XTC)
These regimens are preferred because they're potent, well-tolerated, have minimal side effects, and create high barriers to resistance development 2, 1.
Adherence Requirements
This is critical: ART requires near-perfect adherence (>95%) to maintain viral suppression and prevent resistance. Missing doses allows viral replication and mutation, potentially leading to drug resistance that limits future treatment options.
Key adherence points:
- Take medications at the same time daily
- Never skip doses
- Don't stop therapy without medical guidance
- Report any side effects immediately rather than stopping medications
Monitoring Parameters
After starting ART, monitoring includes:
Viral load (HIV RNA): Check at baseline, 2-4 weeks after starting, then every 3-6 months once suppressed
- Goal: <20-50 copies/mL (undetectable)
- Virologic failure = inability to achieve/maintain <200 copies/mL 2
CD4+ count: Monitor immune recovery every 3-6 months
Drug resistance testing: Perform at baseline and if virologic failure occurs
Metabolic monitoring: Lipids, glucose, kidney function, liver function depending on regimen
Adherence assessment: At every visit
Important Clinical Nuances
"Blips" (transient viral load 20-200 copies/mL) do NOT require regimen changes 2. These are common and don't indicate treatment failure. Only persistent viremia >200 copies/mL constitutes failure.
For treatment-experienced patients with viral suppression who need to switch regimens (due to side effects, drug interactions, or simplification), many can successfully switch to 2-drug regimens like DTG/3TC or DTG/rilpivirine, provided there's no history of integrase resistance 2.
For virologic failure with extensive resistance: Newer agents with novel mechanisms (ibalizumab, fostemsavir, lenacapavir) are recommended, ideally combining at least 2 fully active drugs 2.
Special Considerations
- Hepatitis B co-infection: Must continue tenofovir-containing regimens as these also treat HBV 2
- Pregnancy: ART is recommended for all pregnant women regardless of CD4 count
- Drug interactions: Many medications interact with ART, especially protease inhibitors and some NNRTIs
- Long-acting injectable options: Cabotegravir + rilpivirine given every 2 months is available for select patients who cannot maintain oral adherence 2, 3
Common Pitfalls to Avoid
Never restart ART after interruption without considering resistance testing, though resuming a dolutegravir or bictegravir-based regimen is reasonable while awaiting results if adherence will be good 2.
Don't switch regimens for low-level viremia (20-200 copies/mL) without first assessing adherence and drug interactions - this often resolves without regimen changes 2.
Don't use protease inhibitors as first-line therapy - they have more drug interactions and metabolic side effects compared to integrase inhibitors, though they remain valuable alternative options 2.